Girard derivatives of 5-halosalicylaldehydes



l a tentd Feb. 23, 1954 GIRARD DERIVATIVES F -HALO- SALICYLALDEHYDESWalter A. Gregory, Wilmington, and Edward C.

Hermann, Willow Run, Wilmington, Del., assignors to E. I. du Pont deNemours and Com- Pany, Wilmington, D

ware

el., a corporation of Dela- No Drawing. Application June 10, 1952,

. 1 This invention relates to water-soluble substituted hydrazones ofsalicylaldehyde. It is more particularly directed to2-hydroxy-5-inorganosubstituted benzaldehyde carboxymethyl quaternaryammonium halide hydrazide hydrazones and their solvates and to a methodfor their preparation.

This application is a continuation-in-part of our copending applicationSerial No. 227,119'filed May 18, 1951, now abandoned.

The substituted salicylaldehyde carboxymethyl quaternary ammonium halidehydrazide hydra- :zones of the invention are represented by the formulav where Z is a halogen radical, Y is a quaternary ammonium radical ofthe class consisting of trimethylammonium, triethylammonium, pyridiniumand morpholinium, and X is a member of the group consisting of chlorineand bromine.

The compounds of the invention are prepared by reacting in liquid mediaa substituted salicylaldehyde represented by the formula I OH where Zhas the same significance as in Formula 1 with an aminoacetohydrazidehydrohaliderepresented by the formula mNNHoooHn? i where Y and X havethe same significance as stated above. The aminoacetohydrazidehydrohalides used in the preparation of the compounds of the inventionand represented by Formula 3 are prefw acetic acid is preferred.

Serial No. 292,736

5 Claims. (Cl. 260-240) ner identical with the method'employeclfor'preparing Girards T reagent with'the exception that pyridine issubstituted for trimethy'lamine.

Girards P reagent can be represented graphically by Formula 3, where Yis a pyridinium radical.

The substituted salicylaldehydes used in the preparation of thecompounds of our invention contain an inorganic substituent such ashalogen in the 5-position. Suitable substituted salicylaldehydes are5-chlorosalicylaldehyde, 5-bromo- 'salicylaldehyde;'5-iodosalicylaldehyde, and 5- fluorosalicylaldehyde.

The reaction between the substituted salicylaldehyde and theaminoacetohydrazide hydrohalide is most readily carried out in liquidmedia. While any of a wide variety of normally liquid alcohols andacetic acid-alcohol mixtures may be used, it is preferred to employ analiphatic monohydric lower alcohol, such as, for instance, methanol,propanol, isopropanol, butanol and the like. Hot absolute ethanol is aparticularly preferred solvent for the substituted salicylaldehydes;Alcohol-acetic acid' mixtures are preferred solvents for theaminoacetohydrazide hydrohalides. Y

As catalysts for the reaction between thesubstituted salicylaldehyde andthe aminoacetohydrazide, there maybe used any aliphatic monocarboxylicacid. Such acids include acetic, propicnic, butyric, Valerie and thelike. Glacial The slightly exothermicreaction'between the aldehyde andGirard reagent may also be facilitated by moderate heating, say, bymaintaining the reaction mixture at a temperature vof from about 60-t o100 -C.v The precise temperature employed will, of course, depend uponthe particular reactants and solvent. As a practical matter, thereaction is usually carried out at or slightly under the boiling pointof the solvent.

Usually a reaction period of from 15 minutes to several hours isrequired, but in some cases erably Girards T reagent or Girards Preagent.

.Both of these reagents are commercially available.

drazide hydrochloride, also known as betaine hydrazide, hydrochloride)canbe readily prepared by reacting ethyl chloroacetate andtrimethylamine with hydrazine hydrate by the procedure I described onpage 85 of Organic Syntheses, colllective volume 2, John Wiley '8:SonsIncQNew h 'tYor ,1943;p q

" "Gir'alrds P reagent may be prepared me man- Girards T reagent(trimethylaminoacetohythe reaction may go to completion within a shorttime even at room temperature.

Thesolvates of the compounds of our invention' are obtained by simplycrystallizing the compounds from solvents The preferred solvents forcrystallization of our novel water-soluble like; Of these weparticularly prefer ethanol.

compounds are the lower alkanols, such as, for

instance; methanol, ethanol, -propanol and the While'the alcoholicsolvates are most frequently prepared, other solvates, for instance, thehydrates', maybe prepared. The term solvate is *used herein to includeall-states -of solvation.

3 There may be prepared, for instance, the hemisolvate, the monosolvate,the disolvate, the trisolvate and the like.

conversion omhe solvates oithecompound of the invention 420 :Jfiompqundsthemselves, is readily efiected by treatment of the solvate with aliquid aromatic hydrocarbon, preferably benzene. The product whichseparates from the henzene suspension of the solvatezfimrqa. periqdtufheating is substantially free of any mlcoholeot: solvation.

The compounds of theypresent'fimienflenmm light colored crystallinesolids. ?hey,are,; in general, soluble in water, methanol,:.andaceticncid but insoluble in acetone and ether.

The s-halosalicylaldehyde carboxymethyl quaternary ammonium halidehydrazidehydrazones and their solvates are particularly valuable'because of their curative and systemic dungicidal properties. Thecompounds of the invention have .also given. -.evidence58.5.baQlifiKiQidfiifiIld;P 1213 3 acides and areiusefullimtheetreatment v.of ,cecal coccidiosis in; chickens.

' .;In=order;;to;more..tu1 y .lmderstand.the.,invention itrativeexamples, -,'.Ba f-t -..are b y weight unless :otherwise expressed.

I ,(Carbomymetlrvl),trimethylammomlum tuchlozide.

To a "solution m -1 5.7 par-ts of 5 chlorosalieyl- ,aldehdye in"1:9.i7partsof boiling absolute ethanol,

absolute ethanol 1-73; V parts -ofgglacial acetic acid.Thegresultiriglmixturemaskheatedrunder reflux for aperi-od-bfaboutcne-half =hour "The solution was treated with Darco and--wa$filteredwhile still hot. The solidproduct which-:sepa- ,lected, wash-ed wellwith absolute ethanoLa-then jwith ethergand finaliydried:'Ihe-productsoob- 50 tain'ed had a melting pointayofvz52f c'. (deco.

,AnaLTCalcd. iorv gQiaHflCIaNsOz: :N; 213 .72;

" xmnethzrlpyridiniu chloride, hildmzide zmwhydrazone with5-ehlcresclicylaldehyde warts niisl cialaceti nwra -and wh in w cectedmn afilt r. w she w three-ilz -ne ertionslpnabs lute.ethanmand=-atwosa5-pe t ;nertiqns dimmer nemroductmas air-dried at roomtemperature and weighed 32 parts. It melted withdecomposition at 245 C.

Anal.Ca1cd. for C14H13CI2N3O2+C2H5OHZ N,

11.29; Found; N, 11.49.

.(Carbomymethyl)trimethylammonium chloride,

hydrazide and hydrazone with 5-bromosali- @pgylai eh de To a boilingsolution of 20.1 parts of fi-bromorsalicylaidehydeland 20 parts ofabsolute ethanol wes added a hot solution of 18.4 parts of Girards ll,reagent in a mixture of 134 parts of absolute 20 ethanol, and 18 partsof glacial acetic acid. A ;.white s olid precipitated almost at once (1minute) ,jfIjhe nesulting. solution was; heated *under reflux n I or,one-half; hounand then cooled. I The-product was. collected .91 .firan'd-wa he hree times 25 ..witl,1; 2 (l parts of absolute ethanol andtwice-with 32:11am po ti ns "lin crude pr w air-dried. Yield, "34 parts,LIL-R 250 ideal.

..A' '.l1 l--:Qfil1(5d. I01 C 2Hi'1II3 C) 2G], Br: N, 111198; ,E undLN,1131.0.

1-; Jimme w 'flwo parts of the ethanol monosolvate of 1-(carboxymethylXpyridinium chloride, hydrazide and 'hydrazone with fichlorosalicylaldehyde (produced as in Example 2) was suspended 88 partsof benzene. Fifty-three parts of benzene was then removed bydistillation through a packed 'column. The solid was separated from theresidual suspension by filtration, collected and air-dried. The dryproduct melted at 229- a230, 1C.;and.,=was,substantiallyi free ofalcohol of sol-vation.

- Ana -fi filqd. for fimfi sNaQecl: N. 12,88; :Found:-:N,; 12:81.

-rAlfio zziliustratiye 1th: -.-.QQmQl nd 1 Of -.9u -aventiomare:

(Carboxymethyl)triethylammonium chloride,

hydrazide and =hydrazone with 5-ch-lorosalicylaldehydel-carboxymethylmorphhlinium chloride, hydrazide and hydrazone withfi-chlorosalicylaldehyde (Carboxymethyl)trimethylammonium bromide,amysdrezidemdtlrsrdrazem@Wim: -:91 onmliqfl- (ca bo ymethyl trimethlemmcniu .=h;lq i e,

hydrazide and hydrazone with fi-chlorosalicylaldehyde tgerhet m i ime bl mmqniu chl ri hydrazide and hydrazone with .i' i .-j iodosaligylaldehd We-claim:

. -1 A compound selected: from-the.;group.-con- -:s-istingof '2hydroxyqfi-inorganoebenzaldehyde --carboxymethyl-quaternary ammoniumhalidehy- ,drazide hydrazones representedby the formula:andtheir.hydroxylicsolvates, .whg fezis a halogen radical, Y is :aquaternary ammonium, radical oi. f .t lpgethxlemmqnllimxtnethylammonium,pyridinium and morpholinium, and X is a member of the group consistingof chlorine and bromine.

2. 1-Carboxymethy1pyridinium chloride, hydrazide' and hydrazone with5-chlorosalicyla1dehyde, said compound having the formula I OH 3.(Carboxymethyl)trimethylammonium chloride, hydrazide and hydrazone with5-chlorosalicylaldehyde, said compound having the formula C CH=NNHC oorm uonox 61 4. (Carboxymethyl)trimethylammonium chloride, hydrazide andhydrazone with 5-bromosalicylaldehyde, said compound having the formula5. A process for the preparation of a substituted salicylaldehydecarboxymethyl quaternary ammonium halide hydrazide hydrazone representedby the formula -CH=NNHC o and? i where Z is a halogen radical, Y is aquaternary ammonium radical of the group consisting oftrimethylammonium, triethylammonium, pyridinium and morpholinium, and Xis a member of the group consisting of chlorine and bromine, whichcomprises reacting substituted salicylaldehyde having the formula I OHwhere Z have the same significance as above, with an aminoacetohydrazidehydrohalide represented by the formula mNNHcoomi' i where Y and X havethe same significance as above, in a liquid medium.

WALTER A. GREGORY. EDWARD C. HERMANN.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,536,100 Shappirio Jan. 2. 1951 OTHER REFERENCES

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF2-HYDROXY-5-INORGANO-BENZALDEHYDE CARBOXYMETHYL QUATERNARY AMMONIUMHALIDE HYDRAZIDE HYDRAZONES REPRESENTED BY THE FORMULA